Experimental and Translational Respiratory Group, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Co-operative Research Centre for Asthma and Airways and Hunter Medical Research Institute, Callaghan, Australia.
J Allergy Clin Immunol. 2011 Jul;128(1):160-167.e4. doi: 10.1016/j.jaci.2011.04.005. Epub 2011 May 14.
Glucocorticoids are used as mainstay therapy for asthma, but some patients remain resistant to therapy. MicroRNAs (miRNAs) are important regulators of the immune system by promoting the catabolism of their target transcripts as well as attenuating their translation. The role of miRNA in regulating allergic inflammation remains largely unknown. Blocking miRNA function may provide a new nonsteroidal anti-inflammatory approach to treatment.
To (1) determine the role of specific miRNAs in the regulation of hallmark features of allergic airways inflammation and (2) compare the efficacy of antagonizing miRNA function with that of steroid treatment.
Mice were sensitized and then aeroallergen-challenged with house dust mite to induce allergic airways disease, and alterations in the expression of miRNAs were characterized. Next mice were treated with antagomirs that inhibited the function of specific miRNAs in the lung or treated with dexamethasone and inflammatory lesions, and airway hyperresponsiveness was measured.
miR-145, miR-21, and let-7b have been implicated in airway smooth muscle function, inflammation, and airways epithelial cell function, respectively. Inhibition of miR-145, but not miR-21 or lethal-7b, inhibited eosinophilic inflammation, mucus hypersecretion, T(H)2 cytokine production, and airway hyperresponsiveness. The anti-inflammatory effects of miR-145 antagonism were comparable to steroid treatment.
Our study highlights the importance of understanding the contribution of miRNAs to pathogenesis of human allergic disease and their potential as novel anti-inflammatory targets.
糖皮质激素被用作哮喘的主要治疗药物，但有些患者对治疗仍有抗性。microRNAs（miRNAs）通过促进其靶转录物的分解代谢以及减弱其翻译来作为免疫系统的重要调节剂。miRNA 在调节过敏炎症中的作用在很大程度上尚不清楚。阻断 miRNA 功能可能为非甾体抗炎治疗提供新方法。
（1）确定特定 miRNAs 在调节过敏气道炎症的标志性特征中的作用；（2）比较拮抗 miRNA 功能与类固醇治疗的疗效。
用屋尘螨致敏并激发小鼠，以诱导过敏气道疾病，并对 miRNA 的表达变化进行特征分析。然后，用抑制特定 miRNA 在肺中的功能的反义寡核苷酸（antagomirs）处理小鼠，或用地塞米松处理，并测量炎症病变和气道高反应性。
miR-145、miR-21 和 let-7b 分别与气道平滑肌功能、炎症和气道上皮细胞功能有关。抑制 miR-145，但不抑制 miR-21 或 let-7b，可抑制嗜酸性粒细胞炎症、粘液分泌过度、T(H)2 细胞因子产生和气道高反应性。miR-145 拮抗的抗炎作用与类固醇治疗相当。
我们的研究强调了了解 miRNAs 对人类过敏疾病发病机制的贡献及其作为新型抗炎靶点的潜力的重要性。
